The present invention relates to imidazolidine derivatives, their use in therapy, their preparation, and compositions comprising them.
In men, androgens are associated with the development and maintenance of the primary male characteristics (epididymis, vas deferens, prostate, external genitalia) and secondary male characteristics (development of hair, musculature of the larynx, distribution of fatty tissue, behaviour and libido). In addition, they contribute to muscle and bone development, and also act on the hematopoiesis, the central nervous system and sexual function.
In women, androgens have been involved inter alia in the development and maintenance of bone tissue and libido.
Progressive reduction in levels of circulating androgens in aging men (PADAM—partial androgen decline in aging men) contributes to a specific number of clinical manifestations, including osteoporosis, loss of muscle mass and strength, reduction in libido and sexual dysfunction, anaemia and a change in cognition, mood swings, depression (see Review in: Kaufman J M and Vermeulen A 2005 The decline of androgen levels in elderly men and its clinical and therapeutic implications Endocr Rev. 2005 26:833-76). However, the clinical safety of androgen therapy for cardiovascular and prostate diseases is uncertain. Therefore, androgen supplementation is not recommended for healthy, elderly men (Liu P Y et al. 2004 Clinical review 171: The rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. J. Clin. Endocrinol. Metab. 89:4789-96).
Normal development and functioning of the prostate depend on the androgens and their receptor. Androgens play a significant part in the development and progression of prostate cancers (Heinlein C A and Chang C 2004 Androgen receptor in prostate cancer. Endocr. Rev. 25:276-308). Men affected by prostate cancer and treated by chemical castration suffer bone loss which is 5 to 10 times greater than in patients not treated by chemical castration. This leads to a greater risk of bone fracture (Greenspan S L et al. 2005 Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J. Clin. Endocrinol. Metab. 90:6410-7).
A syndrome associated with the reduction in levels of circulating androgens (ADIF—androgen decline in female) has also been described in women. It can have various causes, including aging, chemotherapy and infection by the AIDS virus. Associated symptoms include: osteoporosis/osteopenia, sarcopenia and muscle weakness, reduction in libido, sexual dysfunction, change of cognition, mood swings, depression. Endometriosis and an increased risk of breast, uterine and ovarian cancers have also been described (Davison S L and Davis S R 2003 Androgens in women. J. Steroid Biochem. Mol. Biol. 85:363-366). The administration of high doses of androgens to women can lead to the appearance of signs of masculinisation, mood swings and acne. These risks must be taken into consideration when administering androgens to women.
Selective modulators of the androgen receptor (SARMs—selective androgen receptor modulators) of non-steroidal structure are molecules which act as ligands of the androgen receptor with a degree of tissue specificity. Substances which are selective modulators of the androgen receptor are particularly desired because they allow the beneficial effects of testosterone on specific organs (bone and muscle tissue) and on the libido to be maintained, and are less likely to lead to secondary effects in specific tissues, such as the prostate in men and the uterus in women. They represent a safer alternative to conventional therapies in any pathologies linked with an androgen deficit, including osteoporosis or sarcopenia, and decline in libido associated with syndromes of the PADAM and ADIF type. They may also be used in the treatment of cachexia induced by specific diseases, such as cancer or AIDS, or in the treatment of muscle loss induced by long-term treatment with glucocorticoids. They may also be used for male contraception and the treatment of hormone-dependent cancers of the prostate and benign hyperplasia of the prostate.
EP-A-704448 discloses imidazolidine derivatives having the structure:
wherein Ar represents aryl optionally substituted by cyano, halogen, trifluoromethyl or an acid or ester radical, X and Y represent O or S, and the encircled H represents an optionally substituted saturated heterocycle comprising oxygen, nitrogen or sulphur atoms. These derivatives are described as having anti-androgen activity.
EP-A-494819 discloses derivatives having the structure:
in which R1 and R2 are cyano, nitro, halogen or trifluoromethyl and X and Y are O or S. These derivatives are described as having anti-androgen activity.
EP-A-578516, WO 95/18794, WO 97/19064 and WO 97/23464 all disclose derivatives having the structure:
in which R1 and R2 are cyano, nitro, halogen or trifluoromethyl, R4 and R5 represent optionally substituted alkyl radicals or form a cycle having from 3 to 7 members optionally containing 1 or more heteroatoms and X and Y are O or S. These derivatives are described as binding to the androgen receptor and as having anti-androgen activity.
WO 03/096980 discloses derivatives having the structure:

in which the radicals R5, R′5, R6, R′6 can respectively form together oxo or thioxo radicals, and G is an optionally substituted aryl radical. These derivatives are described as modulators of the androgen receptor.
Nothing in the art suggests that monocyclic hydantoin derivatives disubstituted by aryl radicals might have SARM activity, owing to the highly conserved nature of the androgen receptors.
Other imidazolidine derivatives having a similar structure have been described in the phytosanitary field. Hence, U.S. Pat. No. 4,977,270 discloses compounds having the structure:
in which R is a lower alkyl, X and Y can be H, halogen, lower alkyl, trifluoromethyl or lower alkoxy, and Z is a carbon or sulphur atom. These derivatives may be used as herbicides.
There is nothing to indicate that such substances might have therapeutic activity.
Aryl-thiohydantoins having the structure:
in which R is an amino-acid radical, R1 can be Cl or CF3 and R2 can be H or Cl are described as anti-nociceptive compounds which act as enkephalinase inhibitors [J. Zhou, Z. Yu and M. Li, Zhongguo Yaoke Daxue Xuebao, 22(6), 330-333, (1991)].